Injectable sustained release composition and method of using the same for treating inflammation in joints and pain associated therewith

Abstract

Described herein are injectable corticosteroid-loaded microparticles, pharmaceutical composition thereof and methods for reducing inflammation or pain in a body compartment such as a joint, an epidural space, a vitreous body of an eye, a surgically created space, or a space adjacent to an implant.

We claim: 
     
         1 . A unit dosage form comprising:
 a plurality of microparticles, the microparticle including:   (1) a crystalline drug core of more than 70% by weight of the microparticle; and   (2) a polymeric shell encapsulating the crystalline drug core,   wherein the crystalline drug core includes one or more crystals of a corticosteroid selected from fluticasone, fluticasone furoate, and fluticasone propionate, and the polymeric shell is in contact but immiscible with the crystalline drug core; and   wherein the unit dosage form releases the corticosteroid over a period of 2-12 months while maintaining a minimum therapeutically effective concentration of the corticosteroid within a body compartment.   
     
     
         2 . The unit dosage form according to  claim 1  wherein the body compartment is a joint, an epidural space, intravitreal space, a surgically created space, or a space adjacent to an implant. 
     
     
         3 . The unit dosage form according to  claim 1  wherein, within the sustained release period of 2-12 months, the corticosteroid is released locally within the body compartment and provides below a quantifiable limit of plasma corticosteroid 7 days after injection. 
     
     
         4 . The unit dosage form according to  claim 1  wherein the plurality of microparticles have a mean diameter in the range of 50 μm to 150 μm and a standard deviation of less than 50% of the mean diameter. 
     
     
         5 . The unit dosage form according to  claim 1  wherein the microparticle comprises 90-98% w/w of crystalline drug core and 2-10% w/w of polymeric shell. 
     
     
         6 . The unit dosage form according to  claim 1  wherein the polymeric shell comprises one or more biodegradable polymers selected from the group consisting of polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA), poly(p-xylylene) polymers, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(ϵ-caprolactone) (PCL), poly(valerolactone) (PVL), poly(ϵ-decalactone) (PDL), poly(1,4-dioxane-2,3-dione), poly(1,3-dioxane-2-one), poly(para-dioxanone) (PDS), poly(hydroxybutyric acid) (PHB), poly(hydroxyvaleric acid) (PHV), and poly(β-malic acid) (PMLA). 
     
     
         7 . An extended release formulation comprising a plurality of microparticles having core/shell morphology, wherein the microparticle includes (1) a crystalline drug core of more than 70% by weight of the microparticle, wherein the crystalline drug core includes one or more crystals of a corticosteroid, a salt or ester thereof; and (2) a polymeric shell encapsulating the crystalline drug core, whereby the polymeric shell is in contact but immiscible with the crystalline drug core. 
     
     
         8 . The extended release formulation according to  claim 7 , wherein the corticosteroid is selected from fluticasone, fluticasone furoate, and fluticasone propionate. 
     
     
         9 . The extended release formulation according to  claim 8 , wherein the polymeric shell comprises one or more of the polymers selected from the group consisting of polyvinyl alcohol (PVA), poly(p-xylylene) polymers (trademarked as Parylene®), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(ϵ-caprolactone) (PCL), poly(valerolactone) (PVL), poly(ϵ-decalactone) (PDL), poly(1,4-dioxane-2,3-dione), poly(1,3-dioxane-2-one), poly(para-dioxanone) (PDS), poly(hydroxybutyric acid) (PHB), poly(hydroxyvaleric acid) (PHV), ethylene vinyl acetate (EVA) and poly(β-malic acid) (PM LA). 
     
     
         10 . The extended release formulation according to  claim 7  wherein said microparticles have a mean diameter of between 50 μm and 400 μm. 
     
     
         11 . The pharmaceutical composition according to  claim 7  wherein said microparticles have a mean diameter of between 80 μm and 150 μm. 
     
     
         12 . A method for treating inflammation or pain in a patient in need thereof, the method comprising administering to the patient the extended release formulation of  claim 7 . 
     
     
         13 . The method according to  claim 12 , wherein the inflammation or pain is due to at least one of osteoarthritis, rheumatoid arthritis or injury induced arthritis, spinal disc protrusion, spinal nerve inflammation in cervical, thoracic or lumbar, chronic low back pain from nerve root compression, diabetic macular edema or uveitis, recurrent capsular contractions or keloid scarring. 
     
     
         14 . The method according to  claim 12  wherein administering the extended release formulation comprises locally injecting to an affected joint, an epidural space, vitreous body, an epidural space, or a space adjacent to an implant having scar tissue of said patient. 
     
     
         15 . The method according to  claim 14  wherein the corticosteroid is released locally within the body compartment and provides below a quantifiable limit of plasma corticosteroid  7  days after injection.